Premature thymic involution with preferential loss of immune CD4+ CD8+ thymocytes involving augmented apoptotic mechanisms occurs in cats affected with GMI and GM2 gangliosidosis. The proposed studies will define the role of ganglioside in the molecular processes of apoptotic cell death in the thymus by evaluating the effects of excess ganglioside in vivo and in vitro on apoptotic induction events involving receptors, transmembrane signal transduction and second messenger systems. Specific metabolic events to be evaluated include: tyrosine phosphorylation, phospholipase C activity, in transcellular calcium homeostasis, calcium mediated events, calmodulin/calcineurin associated events, proteins kinase C activity and cyclic nucleotide concentration. To accomplish these goals, we will study organs and cells derived from cats affected with gangliosidoses and well-defined in vitro model systems based on incorporation of exogenous ganglioside into thymocyte and fetal thymic organ culture. These studies are unique because for the first time it is possible to study ganglioside induced premature thymic involution and accelerated thymocyte apoptosis in a naturally occurring animal disease and results of these studies can be contrasted and compared with in vitro models based on exogenous incorporated ganglioside. These studies will provide new information about ganglioside modulation of thymocyte development, the role of ganglioside in apoptosis, and immune system dysfunction in lysosomal storage diseases.